WO2017113030A1 - Method for producing orthopaedic and dental acrylic materials having antimicrobial properties, using copper nanoparticle technology - Google PatentsMethod for producing orthopaedic and dental acrylic materials having antimicrobial properties, using copper nanoparticle technology
- Publication number
- WO2017113030A1 WO2017113030A1 PCT/CL2016/050079 CL2016050079W WO2017113030A1 WO 2017113030 A1 WO2017113030 A1 WO 2017113030A1 CL 2016050079 W CL2016050079 W CL 2016050079W WO 2017113030 A1 WO2017113030 A1 WO 2017113030A1
- Grant status
- Patent type
- Prior art keywords
- Prior art date
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES, AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
- A01N55/02—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur containing metal atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/02—Use of preparations for artificial teeth, for filling or for capping teeth
- A61K6/08—Use of natural or synthetic resins
Process for preparing dental and orthopedic materials with antimicrobial properties using acrylic technology copper nanoparticles.
FIELD OF THE INVENTION.
The object of the present invention is in a process for the production of a new biomaterial acríllco for manufacturing dental or medical products with antlmicroblanas properties, for use in controlling the growth of microorganisms in the oral cavity or orthopedic treatments, such as removlbles and fixed dental prosthesis, adhesive resin restoration, adhesive ortodóntlco bracket dental resin restoration sealant pits and fissures or orthopedic bone cements based on technology copper nanoparticles and antlmicroblanas properties against dental pathogens, especially Candida albicans, pathogen responsible denture stomatitis or Streptococcus mutans, a bacterium responsible for caries formation, as well as Staphylococcus aureus infections perlprotésicas it generated.
BACKGROUND OF THE INVENTION.
The use of dentures remains the solution most commonly used dental restoration within the population, particularly in low socioeconomic means. Cleaning the prosthesis is essential to maintaining good oral hygiene and to prevent STOMATITIS, chronic inflammation that can result in oral mucosa in contact with the prosthesis, and despite not having a definite etiology, one of its causes it is the fungal infection of Candida. As the vast majority of elderly carriers of prostheses, the ideal hygiene of the prosthesis often is not done properly, in addition to the optical and pslcomotrices limitations, conditions characteristic of elderly patients. The current treatment for this type of infection is administration of oral and topical agents antimlcóticos. However, such agents can have adverse effects for patients, such as malaise and particularly unpleasant tastes. Currently it seeks to develop therapeutic approaches based on the design of prosthetic material, such as obtaining nanocomposite materials with antimicrobial activity. A nanocomposite is a material that combines materials of different nature, as a polymer and a metal, where one has nanometric dimensions. Copper is a known antimicrobial, with antibacterial and antifungal properties; currently they are enhanced with the use of metal particles with nanometric dimensions.
Removable dentures are the most widely used alternative rehabilitation of partially or totally edentulous patients, especially in low-income groups and is the main form of dental rehabilitation in primary care, mainly because of its low cost.
The prosthesis to be an external element, produced in its surface forming a biofilm which can not be eliminated naturally. This biofilm can cause chronic inflammation adjacent to the prosthesis, which is known as STOMATITIS mucosa. This condition is characterized by inflammation and mucosal erythema covered by the prosthesis. It is asymptomatic, and only in some cases presents burning sensation, usually is this surveyed by clinical examination. Although its etiology is not clearly defined, it is mainly associated with the mucosal infection of Candida albicans and poor poor oral hygiene of patients (Gendreau, L. and ZG Loewy, Epidemiology and Etiology of Denture Stomatitis. Journal of Prosthodontics, 201 Jan. 20 (4): p. 251 -260).. Epidemiological studies report a prevalence covering a range of 15-70% showing higher incidence in the elderly and women. In general, it is considered that two-thirds of the carriers removable prostheses, have varying degrees subprosthesis stomatitis.
Candida albicans is a yeast that is normally present in the oral cavity, gastrointestinal tract and vagina, so live commensal. Pathogenicity is regulated virulence factors and the result of its interaction with the host immune response (Schaller M, Borelli C, Korting HC, Hube B. Hydrolytic enzymes as virulence factors of Candida albicans Mycoses 2005;.. 48 (6 ): 365-77). ... 327-35: 9 (7), between virulence factor transcription factors to cell membrane proteins, adhesins, proteolytic enzymes and lipolytic (Calderone RA, Fonzi WA Virulence factors of Candida albicans Trends in Microbiology 2001 are ) and also it possesses the ability to adhere to cells and penetrate the epithelium (Machado A., E. Komiyama, S. Santos, Jorge A., F. Brighenti, Koga-lto C, in vitro adherence of Candida albicans isolated from Patients With chronic periodontitis J Oral Sci Appl 2010;.. 384-387). In addition, Candida albicans is in the form of biofilm on the surface of acrylic dentures, forming a closed matrix microcolonies yeast and hyphae containing a large number of bacteria, such as Streptococcus sps., Extracellular polymers, and even a different phenotype which it is presented in planktonic state. This configuration makes it much more resistant to antimicrobial agents (Candida biofilms LJ Douglas and Their role in infection Trends in Microbiology 2003; 1 1 (1):... 30- 6). In addition, Candida albicans has a high prevalence in the oral cavity, and is commonly found in periodontal pockets, which we may indicate a possible role in the genesis or exacerbation of clinical conditions Periodontal disease (Urzúa B., Hermosilla G .., J. Gamonal, Morales-Bozo I., M. Canals, Barahona S., et al Yeast diversity in the oral microbiota of subjects with periodontitis: Candida albicans and Candida dubliniensis colonize the periodontal pockets Med Mycol 2008; 46.. :. 783-93; and Sardi J., Duke C, Mariano F., I. Peixoto, Hofling J., B. Goncalves periodontal disease in Candida spp: a brief review J Oral Science 2010 Vol 52, No... . 2, 177-185). In patients with refractory periodontitis, 83.3% of periodontal pockets have Candida albicans, which indicates a relationship between it and the infrastructure of periodontal microbiota (Machado et al). .. Canabarro et al, (Canabarro A., Valle C, Farias MR, Santos FB, lazera M., Wanke B. Association of subgingival colonized of Candida albicans and other yeast With severity of periodontitis chrionic J Periodont Res 2013; 48.: 428-432) have hypothesized that the epithelial deep structural disturbance in the periodontal pocket and the immunosuppression caused by the severity of periodontal disease, facilitate subgingival Candida albicans colonization. Therefore there, clear evidence of the coexistence of Candida albicans, responsible for stomatitis and periodontal pathogens. Treatment of first choice for denture stomatitis, is the application of topical and systemic antifungals such as nystatin and Fluconazole. These antifungals may have adverse effects such as headaches, nausea, vomiting and malaise; besides generating discomfort and unpleasant for the patient taste, which increases the discontinuation of such treatment. It is known that treatment with topical antifungals is successful in eradicating contamination by Candida albicans and relieve their symptoms, but if an appropriate and maintained hygiene prosthetics is performed, denture stomatitis will resort once treatment (Gendreau et terminated to the).
Looking for new therapeutic alternatives, it has been observed that the modification of the surface characteristics of the acrylic material, is an effective method to reduce the adhesion of Candida albicans to the prosthesis (Park, SE, et al., Candida albicans Adherence to Surface- Denture Resin modified Surfaces Journal of Prosthodontics, 2008. 17 (5): p. 365-369).. By modifications of the physicochemical properties of medical materials, it is possible to give them antimicrobial properties, thus preventing and controlling infection. In this regard, there have been studies to incorporate antifungal compounds acrylic prosthesis, such as modifying the acrylic surface by impregnating the surface of the acrylic histamines and salivary defensins (Pusateri CR, Monaco EA, Edgerton M. Sensitivity of Candida albicans biofilm cells grown on denture acrylic to antifungal proteins and Archives of Oral Biology chlorhexidine 2009; 54 (6):.. 588-94). Redding et al., Prepared a polymer coating loaded with chlorhexidine, nystatin and amphotericin, the coating being chlorhexidine which outperformed ((S Redding, Bhatt B, Rawls HR, Siegel G, Scott K, Lopez-Ribot J. Inhibition of Candida albicans biofilm formation on denture materials Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2009, Jan. 07 (5):.. 669-72).
Metals have known for centuries antimicrobial properties; and currently, use is being investigated in many applications with the help of nanotechnology and its application in disinfecting surfaces and topical application to gels and pastes. Copper, has been widely used in medicine since the 19th century, it was indicated in the treatment of skin infections, lupus, and was even an antimicrobial agent used to the advent of antibiotics 1932 (Grass, G., C. . Rensing, and M. Solioz, Metallic Copper as an Antimicrobial Surface Applied and Environmental Microbiology, Jan. 77 201 (5): p. 1541 -1547).. Moreover, copper has been used for decades for their antifungal properties (Cioffi, N., Torsi, L, Ditarantano, N., Tantalillo, G., Ghibelli, L, Sabbatini, L, Bleve-Zacheo, T., D ' . Alessio, M., Zambonin, PG, Traversa, E., Copper nanoparticle / polymer composites and bacteriostatic properties antifungal With Mater Chem, 2005, 17, 5255-5262;.. and Palza, H., Jaw, R. Delgado , K., Antimicrobial polymer composites With micro- and nanoparticles copper. Effect of particle size and polymer matrix Journal of Bioactive and Compatible Polymers 5 201, 1 -15).. However, in recent years there has been increasing interest in the use of the antimicrobial properties of this metal, mainly due to the possibility of producing particles with nanometric copper.
The manipulation of the structure and application of materials with nanometer dimensions is what is known as nanotechnology, which is based on control of the properties of the materials to the nanometer scale (1 -100 nm) in order to exploit the various characteristics possessed by the nanosized materials (Ravishankar Rai and Jamuna Bai V. A., Nanoparticles and Their potential application as antimicrobials against microbial pathogens Science. research and technological communicating current advances 201 1 1 (1). p. 10). It is expected that with the development of nanotechnology significant progress is made in the biological and biomedical sciences, providing tools to achieve understand the structures of materials and fabrics and designing technologies to explore power, treat and possibly reconstruct (Ahmed, W ., A. Elhissi, and K. Subramani, Chapter 1 - Introduction to Nanotechnology, in Nanobiomaterials in Clinical Dentistry, KSAK Hartsfield, Editor, 2013, William Andrew Publishing p 3-16).... Nanoparticles by size acquire new properties relative to those observed in micrometer-sized structures. These properties are determined by the effect generated by the atoms located at the surface layer of the structure and to present a greater surface area to volume ratio of the nanoparticles, compared to that given in microstructures or macrométricas (Ren, G., et al, Characterization of copper oxide nanoparticles for antimicrobial applications International Journal of antimicrobial Agents, 2009. 33 (6):.. p 587-590).. One of the most studied is the metal nanoparticles Silver (AgNP), which have demonstrated antibacterial properties against Escherichia coli, Staphylococcus aureus, and Klebsiella pneunomiae (Ravishankar et al.).
Regarding copper nanoparticles (CuNP) have observed improved antimicrobial properties compared to micro (Theivasanthi, T., Studies of Copper Nanoparticles Effects on Micro-organisms. Annals of Biological Research, 201 1. 2 size (3 ): p 368- 373).. They have also been effective in killing numerous strains of nosocomial infections, but the need for the controlled release of ions to the local environment is observed, for optimum antimicrobial activity (Ren, G., et al.). The antimicrobial properties of CuNPs been evaluated so far against the bacteria Escherichia coli, Staphylococcus aureus, Klebsiella pneunomiae, Listeria monocytogenes and Pseudomonas aeruginosa; as against the yeast Saccharomyces cerevisiae. However, regarding oral bacteria it has not found evidence in the prior art.
Studies concerning the bactericidal mechanism copper nanoparticle, indicate that the effect is attributed to its small size and large contact surface in relation to its volume, allowing it to easily interact with microbial membranes (Chatterjee AK, Ruchira C, Tarakdas B. Mechanism of antibacterial activity of copper nanoparticles Nanotechnology 2014; 25 (13):.. 135101). A method widely accepted action is cell death by contact, which would be produced by a series of successive events, since damage to the cell membrane, the input copper into the cell, the formation of reactive oxygen species by copper ions involved in redox reaction and subsequent degradation of DNA, producing cell death (Grass et al.). In a 2014 study, new information about the mechanism of antibacterial action of copper nanoparticles were reported. In the study of Escherichia coli CuNP on a change of morphology toward a filamentous bacterial formation and subsequent cell death it was observed. This effect is attributed to the cellular response caused by an overproduction of reactive oxygen species, resulting in a considerable lipid peroxidation, protein oxidation and degradation of DNA (Chatterjee et al.) - However, the authors also conclude that probably there is no single mechanism of bactericidal action for CuNP, the active agent may be either the same or nanoparticle metal ions which are released from the particle. Recent evidence suggests that increased antimicrobial effect would be produced by the release of ions from the nanoparticles (Palza, H., Antimicrobial Polymers with Metal Nanoparticles. Int. J. Mol. Sci. 2015, 16, 2099-21 16).
Furthermore, no studies have been performed with copper nanoparticles on the effect with Candida albicans, but studies AgNP are, where they have reported the effects of AgNP used topically biofilm Candida albicans (Monteiro, DR, et . al, Silver nanoparticle colloidal stability: influence on Candida biofilms FORMED on acrylic denture Medical Mycology, 2014. 52 (6):.. p 627-635); and Candida glabrata (Silva, S., et al, The effect of silver nanoparticles and nystatin on mixed biofilms of Candida glabrata and Candida albicans on acrylic Medical Mycology, 2013. 51 (2):... p 178- 184) formed on acrylic surfaces exhibiting biocidal effects for both strains.
Because the antimicrobial ability of these particles the ability to modify the acrylic graft material incorporating metal to its polymer matrix nanoparticles explored. Kamikawa et al. evaluated the adhesion of Candida albicans and Candida glabrata on modified dental acrylics with a polymer coating loaded with AgNP, observing a significant reduction in the growth of colonies of Candida albicans (Kamikawa, Y., et al., In Vitro Antifungal Activity against Oral Candida . Denture Base Species Using a Coated with Silver Nanoparticles Journal of Nanomaterials, 2014. 2014: p 6).. In other approaches it has been tried incorporating AgNP inside acrylic resin. These materials have the capacity to release in a controlled manner the active agent and thus control the growth of microorganisms on the surface of the prosthesis. The existence of a dental prosthesis with these antimicrobial properties, would prevent and treat stomatitis, unlike antifungal therapy only treats the disease. Using this strategy modification of acrylic material (Nam KY, Lee CH, Lee CJ Antifungal and physical characteristics of modified denture based acrylic incorporated with silver nanoparticles Gerodontology 2012; 29 (2):... E413-E9), incorporated AgNP to acrylic dentures, they mixing colloidal suspensions of silver with acrylic, through use silver contents between 20- 30% by weight, achieved a significant inhibition of Candida albicans relative to control. They also observed a sustained release of silver over time, maintaining antifungal properties. However, the dark color of the resultant nanocomposite material produced by the particles AgNP is clearly unfavorable aspect from the point of view aesthetic dentistry.
Furthermore, the CuNPs have been used for preparing various polymer nanocomposites with antimicrobial properties. In addition, polymers such as polivinilcetona loaded CuNP, where the ability to release metal slowly and controlled, and also inhibit the growth of bacteria and fungi such as Saccharomyces cerevisiae was observed were studied; and the antimicrobial activity is directly correlated to the concentration of nanoparticles (Cioffi et al.). Other polymer matrices are studied plant and bacterial celluloses loaded with nanostructures, such as nanowires and CuNP showing bactericidal activity against Staphylococcus aureus and Klebsiella pneunomiae. This polymer with potential application for use in wrapping papers (Theivasanthi et al.). With respect to polymers modified acrylic CuNP, Liu et al. (Liu, YY., Liu, DM., Chen, SY., Tung TH., Liu TY., In situ synthesis of hybrid nanocomposite With highly amoorphous order metallic copper nanoparticle arranged in poly (2- hidroxyethyl methacrylate) and Its potential for blood-contact use. Acta Biomateralia, 2008, (4), 2052-2058), incorporated CuNP in a matrix of poly (2-hydroxyethyl methacrylate) (pHEMA) used in the manufacture of biomedical devices with cardiovascular application. The results show that incorporation (0.03-0.15% copper) CuNP reduced platelet adhesion, thereby avoiding the production of blood clots, however in this work no antimicrobial properties of nanocomposite material is evaluated. Regarding the antimicrobial mechanism of polymer / metal nanocomposites a release mechanism or corrosion of nanoparticles in the matrix due to diffusion of water molecules from the external environment is postulated ions. The diffusion of water molecules has been observed even in non-polar polymeric matrices, such as polyethylene and polypropylene (Palza et al., And Ton-That, TM., Jungnickel, BJ. Water diffusion into transcrystalline layers on polypropylene. J. Appl . Polum. Sci. 1999, 74, 3275-3285). Also, with the passage of time, corrosion of the polymer would occur, which would also release ions, contributing to the sustained release of copper in time (Palza et al.).
The incorporation of metal nanoparticles on dental acrylic to impart antimicrobial properties, have advantages over traditional organic antimicrobials. Antibiotics produce adverse effects and microbial resistance systemically in patients, so the prior art poses new antibacterial investigate alternatives (Nam et al.). Moreover, in a study chlorhexidine they were incorporated into dental acrylics, finding that such compounds undergoes rapid release in aqueous medium, also high release of residual monomer incomplete polymerization (Wilson, SJ1, Wilson, HJ found. . The Release of chlorhexidine from dental acrylic resin modified J Oral Rehabil 1993 May; 20 (3): January 31 -9). In addition, dental agents such as chlorhexidine have been studied in gels methylcellulose and polyacrylic acid, having a temperature between 22 and 42 release ° C. (Musial, W., Kokol, V., Voncina, B., Deposition and Release of Chlorhexidine from non-ionic and anionic polymer matrices. Chemical Papers, 201 0 (64), 3, 346-353). In general, the incorporation of organic antimicrobials has a high release rate with increasing temperature, which can expect high loss of active to be used in conditions thermopolymerization acrylic prosthesis (high temperature 90 agent ° C, under pressure). These aspects of stability of the antimicrobial agent under conditions of heat curing could be improved by using metal nanoparticles, such as copper.
It is known that the oral cavity is a habitat type where a set of microorganisms (microbial community) live. Where the manifestation of dental caries is complex-mediated mechanisms are initiated by factors, which include genetic, behavioral, environmental and microbial. In the case of microbial factors, the presence of pathogens is critical to the initiation and progression of caries lesions without bacteria no injury. In fact it is a polymicrobial infectious disease, where each individual bacterial species may contribute collectively to the total biocommunity cariogenicity of dental plaque (dental biofilm) associated with caries. Intrinsic nutrient sources for microorganisms in the oral cavity are the materials found around the teeth, exudates, degraded epithelial cells and saliva components, certain salivary proteins provide amino acids which influence the growth of Streptococcus mutans and Streptococcus sanguis; saliva of subjects with tooth decay better influences the growth of Streptococcus mutans. Besides the food we eat remains in the oral cavity, it serves as a nutrient source extrinsic to the oral microflora.
Dental caries is an infectious disease of multifactorial etiology, where microorganisms organized in a biofilm called plaque, are a factor in the development of caries lesion, and this represents the late sign of disease. At each stage of lesion progression microbial species predominate as a result of a succession of microorganisms. For healthy subjects free caries has been observed the predominance of organisms other than those associated with disease, such as Streptococcus sanguinis. However, in subjects affected by dental caries streptococci mutans belonging to the group have been the preponderant during initiation and progression of the lesion, especially Streptococcus mutans, while Lactobacillus and Bifidobacterium predominate in the advanced stages of the injury.
Another type of microbial disease affecting the oral tissues, is related to the organism Candida albicans, which is a yeast species causing denture stomatitis which is caused by the use of a dental prosthesis; and it said microorganism usually develops due to poor adjustment of said prosthesis or poor cleaning it. The denture stomatitis related to C. albicans is a non-specific antigens inflammatory reaction, toxins and microbial enzymes are produced by colonizing organisms, which is a serious infection of the oral mucosa is a common and recurrent disease it affects up to 67% of users of dental prostheses. It is known that factors such as poor oral hygiene, high carbohydrate intake, reduced salivary flow, continuous use of the prosthesis, aging, malnutrition, immune suppression, radiation, diabetes mellitus and possibly antibiotics, increase susceptibility to the C . albicans.
Biomaterials can be artificial or biological origin. In the first case we can mention the metallic, polymeric and ceramic materials. Metal implants, together with its alloys are most commonly used for orthopedic implants (nails, wires, plates), dental implants (screws), and should possess high resistance to mechanical wear and be able to withstand the appropriate charge for function. The metals used to manufacture these implants are: stainless steel, cobalt alloys with chromium, molybdenum and nickel, pure titanium (Ti) and its alloys with aluminum and vanadium. With respect to biological biomaterials, can be named for example bone fragments, skin grafts, extracellular matrix to (human or animal) stem cells.
Currently, with the advent of nanotechnology they have been developed certain nanomaterials, particularly nanoparticles (NPs) inorganic, having a marked microbicidal effect on a wide variety of microorganisms, such as viruses, bacteria and fungi. The microbicidal capacity of NPs is linked to the nature of the material and certain intrinsic characteristics thereof, as their nanometric dimensions (which allows them to be internalized more easily in microorganisms) and high area / volume ratio enabling greater contact and interaction with such microorganisms. The metal NPs have shown microbicidal properties are the most important silver, zinc oxide, copper or iron oxides. The first three substances already have this property in their macroscopic form, while iron oxides are only be microbicides in nanostructured form. NPs have microbicidal mechanisms of action completely different from traditional antibiotics, thus providing a promising alternative. Bactericidal mechanisms of metal NPs have not been fully elucidated, but have been postulated various types of mechanisms. Among which may be mentioned disturbances in the functions of the cell membrane (which alter the permeability and cellular respiration), the entry of the nanoparticles to the cell, which creates an alteration in the functions of proteins and DNA or the production of oxidative species due to the presence of NPs inside the cell. It is easy to make a comparative analysis of the literature data as the bactericide will depend on a variety of factors which include: the size and shape of NPs, chemical composition, the coating and its load surface potential and the concentration of NPs used.
The preparation of said dental material is based on the incorporation of copper nanoparticles (CuNPs) the material by in-situ formation from precursor copper or by direct synthesis prior addition. The advantage of this technology lies in the fact that the commercial process presently used for the production of the prosthesis is not altered, since it is based on the same resin without altering currently used. These new prosthetic nanoparticle technology copper, devices presented antifungal properties which would help prevent and / or treat denture stomatitis and reducing the amount of cariogenic bacteria users with dentures. In short, the technology proposed for the preparation of material antimicrobial denture, considered the synthesis and / or incorporation of the CuNPs during the preparation of prostheses currently marketed which would facilitate the penetration of our approach to the market.
They have made efforts to provide antimicrobial action devices and dental materials, which can include:
RU 2444349 describes document a modified adhesive composition denture fixation, which contains weight percent of polyvinylpyrrolidone-5, -15 polyacrylic acid, glycerol-4, cetrimide antiseptic; sodium alginate-5, balsam fir-10, silver nanoparticles size 1 to 5 nm, and the rest distilled water. The simplicity, safety and efficacy of the composition of modified adhesive developed for fixing the denture can use in common orthopedic practice, wherein the adhesive composition provides substantial reduction in length adaptation of patients without teeth with complete dentures, no cause any toxic action on the tissues of the area and the support body of the prosthesis as a whole and show optimum adhesive properties, remaining unresolved for a long time with callente food intake.
US 2013014671 describes a antlmicroblano dental material characterized by the addition of about 0.1 to 0.5% by weight of metal particles antibacterlanas a zirconium oxide (Zr0 2) as a substrate powder antlmicroblano dental material. The metal material has excellent properties antlbacterianas release ions, which include: silver, gold, platinum, paladlo, iridium, titanium, copper, tin, antimony, bismuth and zinc, especially preferred to use silver, copper and titanium. After being thoroughly mixed and slnterizado from metal particles antibacterlanas it diffuses naturally in the substrate zirconia, so that it has a antlmicroblana dental implant material denture or prosthesis or any other oral reconstruction.
US 6267590 describes document a dental appliance, such as the type of orthodontics, to be placed in the mouth and having an inorganic antimlcrobiano agent on a surface, wherein the agent is preferably a zeollta. The dental appliance may comprise metal or a polymer (pollcarbonato) and the agent may be present in a coating applied to the surfaces of the apparatus to be contacted by liquid or solid in the mouth. The apparatus may be a resin or an elastomer pollmérica incorporating the agent. A preferred agent is antlmicroblano ceramic particles (eg, particles zeollta) antimlcrobianos containing metal ions, for example, silver ion, as the active agent.
US 3,476,854 describes document a formulation of a acríllco materials (alkyl methacrylates), slllcona resins, copolymers vlnilo and pollamida to form coatings or fabric conditioners denture, loaded with antifúnglcos compounds of zinc carboxylates (undecylenate ) which is dispersed in said resin, wherein said antlfúngico agent is selected from heavy metal salts of monocarboxíllcos fatty acids, to fatty acids of medium chain length, benzoic acid, benzyl benzoate, salicylic acid and benzyl salicylate and said antifungal agent present in said resin in an amount effective to retard the growth of fungi in said composition being, and said amount being at least about 1% by weight of said composition.
EP 2536379 A2 describes an antibacterial dental prosthesis comprising a polymeric substrate with a component functional polymer and a releasable antifungal agent and which is attached to the functional polymer component such that the antifungal agent is slowly elutes from the polymeric component functional for an extended period of time.
EP 0081962 A2 describes a solid composition compressed for cleaning dentures is very effervescent when added to water, which is composed of a mixture of perborate, dichloroisocyanurate and an alkali, resulting in a cleaning solution of pH eleven .
EP 0400080 B1 describes a method for providing a dental prosthesis with a protective coating, which comprises applying to said prosthesis an aqueous dispersion of a coating of, antibacterial denture nontoxic polysaccharide which reduces the adhesion of cells Streptococcus salivarius denture acrylic resin by at least 25% compared to a control without Revesti.
EP 1 003791 discloses a formulation A4 of a cleaning and antimicrobial adhesive cream for dental prostheses, comprising nystatin or a combination of 8-hydroxyquinoline (or its salt) and at least one salt of copper (II), wherein said formulation is to prevent denture stomatitis by inhibiting Candida albicans.
US 4,332,791 describes document an aqueous composition containing toothpaste at least one soluble copper compound in water and at least one polishing agent, most of the polishing agent is silicon dioxide. 0471396 EP discloses an oral composition comprising a bicarbonate salt, a copper compound present in an amount effective to inhibit bacterial growth and complexing agent present in an amount effective to stabilize the copper compound amount.
US 201 1 / 0,229,534 A1 describes lations form or oral care comprising anti -i u na rritante amount of salt or salt na lato ici yu na effective amount of a flavoring agent, and a host anti -inflamatoria of an irritant, for example ketorolac. December has lations form or oral care can be raised in various devices useful for treating and / or provide for the i go rritación of ucosas such as m or lceraciones.
US 9034354 B2 describes coatings antibacterial and antimicrobial surface and dental materials using the antimicrobial properties of chalcogenide copper and / or copper halide (CuQ where Q = chalcogens including oxygen or halogen, or none). Wherein an antimicrobial barrier is created by incorporating nanoparticles of suitable size CuQ and a necessary and sufficient to create a unique bioelectrical concentration environment. The results of the single bioelectrical environment biocidal efficacy is through a multi-factorial mechanism comprising a combination of intrinsic quantum flux of copper ions (Cu 0, Cu 1+, Cu 2+) and high electron sink surface to volume provided by the nanoparticles. The result is the quantum constant flow manifests copper and sets the antimicrobial environment to prevent or inhibit the growth of bacteria. CuQ presence results in the inhibition or delay of bacterial destruction and endogenous enzymatic decomposition zone inter-diffusion resin, the integrity of which is essential for the longevity of the dental restoration. Thus, this invention is directed to a bacteriostatic / bactericidal and anti-collagenolytic used to control the invasion and proliferation of microorganisms adhesive. Regarding the use of copper for controlling the denture stomatitis, A4 EP 1003791 describes a formulation of an antimicrobial denture adhesive cream, wherein the active ingredient of the adhesive consists of 8-hydroxyquinoline (0.0001 -0, 5%) and a copper salt II (0.001 -0.3%) is one that produces increased activity against C. albicans by in vitro assays.
The copper also appears as an active agent in the formulation of toothpastes properties for controlling microbial plaque. Thus, US 4,332,791 describes document toothpaste containing silica and a copper salt (0.001 -5%) as active components, while in EP 0471396 A1, the active fraction consists of a copper salt (0.01 5%), sodium bicarbonate and an alkylamine acting as stabilizing the metal ion. have also been used salts such as copper salicylate (0.05-0.3%), the formulation for mouthwashes and oral ulcers control irritations, such as described in US 201 1 / 0,229,534 A1.
Most dental materials currently used for the preparation of restorations, implants, orthodontic elements, prostheses and other; They do not have antimicrobial properties that will control the activity of microorganisms in the oral cavity. Therefore, the prior art does not disclose the preparation of dental prostheses based on acrylic (PMMA) with copper using this element as an antimicrobial additive, whether as a salt or nanoparticle. Neither product formulation or dental materials are detected and oral health therapies using copper as nanoparticle.
DETAILED DESCRIPTION OF THE INVENTION.
The present invention is aimed at developing a new material for manufacturing a dental prosthesis with antimicrobial properties, preferably to prevent the denture stomatitis caused by the pathogen Candida albicans and reducing bacteria such as Streptococcus mutans, pathogen responsible for the initiation and progression of caries formation. In addition, preferably the synthesis of antimicrobial prosthesis material described using copper nanoparticles as an antifungal agent by incorporating copper particles into an acrylic thermosetting resin, which will generate a graft material with antimicrobial properties especially against Candida albicans and particularly against Streptococcus mutans, so to maintain the mechanical properties, color and cytocompatibility.
In a preferred embodiment, the present invention provides a material denture nanocomposite CuNP / PMMA antimicrobial based copper nanoparticles (CuNP) and polymethylmethacrylate (PMMA), comprising the CuNP dispersed in said resin and formed in situ during the process thermopolymerization from a copper salt as the precursor.
In other preferred embodiments, the present invention provides a nanocomposite material including CuNP / PMMA thermopolymerization based copper nanoparticles (CuNP) and polymethylmethacrylate (PMMA); wherein said nanocomposite applications materials (acrylic polymers CuNP) are performed in: fixed or removable dental prosthesis; resins dental restoration; resin adhesive (adhesive for bonding resin restoration to the tooth), sealing pits and fissures (sealant acrylic is used to prevent the development of caries from minor cracks in teeth, widely used in children), adhesive orthodontic (used to bond the bracket on the tooth surface), glass ionomer (a versatile material in dentistry, which can be used as a restoration time in adults or permanent in children, or as a cementing agent other dental materials) and bone cement or surgical (self-curing acrylic used for fixing prosthetic devices to bone or craneoplasty).
In another preferred embodiment, the present invention comprises an antimicrobial dental sealant comprising a dental sealant; and an antimicrobial dental resin comprising an antimicrobial amount of copper nanoparticles (CuNP) diffused therein. In another preferred embodiment, the invention provides a method to prevent secondary tooth decay including applying a dental resin nanocompósita based copper nanoparticles (CuNP) restoration.
In another preferred embodiment, the invention provides a method for preventing or inhibiting dental caries comprising applying an antimicrobial dental sealant on pits and fissures of a tooth, wherein the antimicrobial sealer includes an antimicrobial dental resin comprising an antimicrobial amount of nanoparticles copper (CuNP) diffused therein.
In another preferred embodiment, the present invention provides a method for inhibiting or limit microbial growth in the area of contact enamel orthodontic bracket comprising using an adhesive antimicrobial orthodontic of copper nanoparticles (CuNP) diffused therein.
Note that in each of the preferred embodiments, the copper nanoparticles (CuNP) have a particle size of copper from 40 to 100 nm.
The existence of a dental prosthesis with these antimicrobial properties, would prevent denture stomatitis and caries formation. Unlike the current antifungal therapy aimed at treating the disease, the use of an antifungal prostheses have the dual effect of preventing and treating these diseases. The antifungal properties of the new material based prosthesis copper nanoparticles, control the growth of microorganisms on the surface of the prosthesis, killing the colonies of the pathogen (fungicidal effect) as well as reducing adhesion on the surface of the prosthesis (effect antifouling). These antimicrobial conditions provided by the new prosthetic material should considerably reduce chances of getting these diseases. Additionally, users who manifest the pathology could replace conventional dental prosthesis by the antimicrobial device, which constitute a new treatment of denture stomatitis without the inconvenience caused by traditional antifungal therapy. Prevention of denture stomatitis, would significantly improve the quality of life of prosthesis wearers and patients would avoid investing in overtime costs and dental treatment involving pathology. In particular, would have a significant social impact on oral health high elderly population; as well as the most vulnerable socioeconomic groups that use removable prosthesis as the only alternative to dental rehabilitation.
The removable prosthesis is currently the most widely used alternative rehabilitation partially or totally edentulous patients, especially in low-income groups, and is the main form of dental rehabilitation in primary care services in the country. Globally, these types of tools is widespread throughout the population in a high percentage. Thus, in countries like Holland 1 9% of the population over 16 years using prostheses [Central Bureau of Statistics (Statistics Netherlands), Web magazine, 28 December 2005], in Spain 9 million users are estimated (20% of the population) [U & N AC Nielsen, Market Analysis, blog Oral Health (Dentaid), http://www.blogsaludbucal.eS/archive/2010/10/25/protesis-dentales-comodas-y-limpias .html (2009)], whereas in the United States more than 35 million people use full or partial dentures [the National Center for Health Care Statistics http: //www.cdc.qov/nchs/) 1. In Chile, the use of dental prostheses appears in 50% of plans "Flow Chart dental treatment for adults 60 years" of "Clinical Oral Health Comprehensive Guide for Adults 60 years," MINSAL (2010). Data from the "National Health Survey" conducted in 2003 indicate that more than 60% of the population over 65 years is a user of dentures.
As any external element, prostheses must have a mainly linked to cleaning maintenance, which is not always done properly, which is increased in the case of older adults. This shortcoming favors the formation of microbial plaque that generates multiple instances inflammatory conditions of the oral mucosa, whose culture media are food residues deposited on the prosthesis. This results in the generation of a chronic inflammatory process of the mucosa adjacent to the prosthesis, known as denture stomatitis. The diagnosis of this condition is mainly clinical symptomatology and varies from asymptomatic to conditions with pain and / or burning of varying intensity in compromised oral mucosa. The denture stomatitis is one of the disorders that most often diagnosed in oral pathology, and is an oral health problem that requires alternative prevention and / or control more effective. This pathology can develop into a hyperplastic lesion if not treated. It usually occurs in the lining support, in patients with removable prostheses, commonly which they are in poor condition. The denture stomatitis delimits and prevents optimal use of removable dentures as well under this clinical condition that the user must be treated according to the guide with specific topical antifungals, generating a significant economic burden to the service responsible for care. Studies show that the prevalence of denture stomatitis ranges from 25-65% [N. Gonzalez, Jesus I. et al., Prevalence of denture stomatitis, AMC, Camagüey, v. 13, n. 1, Feb. 2009, and Zissis A, S Yannikakis, Harrison A. Denture stomatitis Comparison of prevalence in two population groups, Int J Prosthodont 2006 Nov-Dec; 19 (6): 621 -5], engaging subjects whose ages range between 25 and 90 years. The disease has a prevalence of 40% in people aged 50 to 65 years old and has a prevalence in females with a ratio of 4: 1 [The denture stomatitis, Notes Odontochile, www.odontochile.cll. It is generally considered that two thirds of the carriers removable prostheses denture stomatitis have a varying degree.
Although stomatitis may be due to local factors such as misalignment of the prosthesis, disturbed immune system or snuff consumption; this disease is mainly caused by a microbial infection. It is estimated that a large percentage is the result of an exaggerated response of the body against infection by mucosal microorganisms that colonize the surface of the prosthesis, in most cases fungi of the genus Candida. These pathogens are commensal oral microbiota members, and are present in about 40 percent of the population without causing problems in most of these. However, uncontrolled multiplication product of a period of immunosuppression or by the presence of local factors, allows colonization of the patient's tissues. This generates changes in oral mucosa manifested by a series of symptoms and signs that are generically known as Oral Candidiasis. Candidiasis chronic atrophic, is one type of oral candidiasis is directly associated with the use of removable dentures, and is distinguished from other types of candidiasis because it occurs in areas that are covered by the apparatus, such as the hard palate, observing as a erythema and edema in the area. Chronic candidiasis atrophic may manifest as well-defined hyperemic macula (Type I), as a diffuse erythema of part or all of the area covered by the prosthesis (Type II), or as a papillary hyperplasia (granular) which commits the hard palate or alveolar (Type III). The most relevant microorganisms responsible for this infection are species of Candida species such as C. glabrata, C. tropicalis, C. kefyr, C. krusei and C. guilliermondii, Candida albicans however is that most often is isolated from lesions of the oral cavity [Williams DW, Kuriyama T, Silva S, Malic S, Lewis MA (2002), Candida biofilms and thrush: treatment and prevention, Postgrad Med J, 78: 455-459]. It is considered that C. albicans colonizes first the back of the tongue and, from there, is able to invade other sites oral cavity mucosa, teeth or dental materials are colonized secondarily [Webb BC, Thomas CJ, Willcox MD, Harty DW, Knox KW (201 1), Candida-associated denture stomatitis, Aetiology and management: a review. Part 1; Factors Influencing distribution of Candida species in the oral cavity, Aust Dent J 39 (1 1): 1 -9 71]. C. albicans is the species that expresses a greater amount of virulence factors associated with pathogenicity, among which are: ability to adhere to host cells (mucoadhesion), secretion of proteinases (tissue destruction), and changes in morphology from yeast and hyphae pseudohyphae. The main mechanism that allows these microorganisms can be maintained in the oral cavity, is by forming biofilms on surfaces. The biofilm protects yeast mechanical removal action that produce saliva, also functions as a protective barrier against the penetration factors of host immune response, as well as antimicrobials administered. Candida initially adheres to surfaces in the form of yeast, then proliferate by growth of yeasts and filamentous generation extensions in the form of multicellular hyphae. The existence of the denture stomatitis not only affects the quality of life of a large part of the population (60% of 20% of the population that wear dentures), especially in the elderly, affecting their normal functions such as chewing, phonation and aesthetics, but generates a large direct economic cost. This cost is related to the need for extra dental care, and subject to controls and treatments that can consider device replacement. From the point of view country, services of public attention this condition necessitates special planning and the use of additional resources.
Current therapies, above, to control stomatitis, are effective provided that there is a compromise of patients with treatment, and is achieved modify the conditions that allow uncontrolled proliferation of microorganisms. However, according to clinical experience, these control measures generally are not met, which results in a high incidence of this disease in the Chilean population, reaching 22.3%. Treatment usually is complex which involves a large economic cost to patients, because of the need to attend frequent the dentist way, as well as the use of drugs and materials to restore tissue health. Considering that the main users of this type of device are social groups with lower incomes, the need to seek alternatives to reduce the incidence of candidiasis associated with the use of removable prosthesis.
Treatment of a patient with oral candidiasis generally considered various aspects. As an essential part of the treatment, the patient is instructed in proper hygiene technique that allows complete removal of biofilm, both from the surface of the mucosa and from the dental prosthesis. Besides procedures mechanical removal of biofilm, use of mouthwashes possess activity against Candida species such as chlorhexidine and triclosan is recommended. Patients are also emphasizes the importance of quitting, because the snuff generates a higher incidence of oral candidiasis. In addition, it seeks to detect and correct any deficiencies in the diet, such as a inaproplada carbohydrate intake. In most patients, these measures could be enough to control the infection, but there is a significant percentage in which despite these interventions are met, it is not possible to control the disease. This is because there are other factors involved, and that can not be modified. These include HIV patients or those who have undergone organ transplantation, and that are under treatment with immunosuppressants. In these particular cases and those in which the disease is not controlled by the initial steps, one resorts to treatment based on the use of antlfúngicos agents. Currently, one be of antlfúngicos that have proven effective for treating candldiasls such as pollenos (Nistatlna, Anfotericlna B), triazoles (Fluconazole, Itraconazole, Vorlconazol and Posaconazole), Equlnocandinas (Caspofunglna, Micafunglna, Anidulafunglna) are known and Flucltosina. These drugs can be administered topically or slstémica manner. However, use can also result antlfúngicos be of adverse, such as headaches, nausea, vomiting and gastrointestinal malaise reactions. Because of their mechanism of removal, some drugs may be hepatotóxlcos slstémicos, or generate neutropenla. The sistémlcos anifúnglcos general also nteractúan with other medications, so you must perform a complete medical history before prescribing. It is for this reason that dentists try to avoid using slstémicos antlfúngicos, and only prescribed in situations clearly justified. For less aggressive candldiasls, topical antlfúngicos are the first line therapy. These substances generally have a favorable response to be used in direct contact with the lesion. However, topical administration are usually ineffective compared to slstémico use, due to the need for frequent application of the drug in the affected area, which is not always done by the patients. Additionally, topical agents are characterized by very unpleasant flavors, generate discomfort during use and maintained for a short time in contact with the oral mucosa. Moreover, also it can cause various adverse reactions by contact of the drug with the lesion, in this case the most Important correspond to Mucosal irritation or skin, change in taste and burning area. In a recent study published by AL-Dwairi et al., It is concluded that exposure of prosthesis acrylic (PMMA) with topical antifungals, can also affect the roughness, wettability and surface free energy of the prosthetic material. The results of this study show that changes in the antifungal acrylic paradoxically increase the adhesion of C. albicans in the material.
In short, the high impact of this disease and growth is forecast due to the steady increase in the most vulnerable such as the elderly population causes a demand for innovative solutions that help slow it down is generated. Within this context, the opportunity arises to develop a new type of prosthesis containing antimicrobial agents to help minimize the prevalence of this disease. Thus the development of new resins with copper particles to generate such materials are capable of releasing in a controlled manner the active agent (metal ions) and thus prevent the development of this disease is proposed.
Thus, an approach to the development of antimicrobial copper-based resins having a scientific and technological challenge from several points of view. The basis of the challenge is based on the need to develop nano particles of copper or nanostructured which are stable in the polymeric matrix used in dentures. For this it is necessary to find the best copper nanoparticle plus the best methodology for preparing the polymeric composites incorporate. In addition, this composite must provide a controlled release of copper ions at a rate that is less than the minimum required to avoid toxicity and near necessary to have a biocidal effect concentrations. All this, without altering the polymerization process and / or curing of the resin, or the current commercial process of preparing the prosthesis. From the technological point of view, the new prosthesis should maintain the structural properties of the original resin, without substantial alteration in its color or appearance. This poses new challenges related to particle type copper concentration and distribution in the polymer matrix. In the present invention an antimicrobial prosthesis material is developed using elements and techniques currently offered by nanotechnology. Particularly, the use of metallic copper with nanometric particle size, unlike the use of salts of copper ions more traditionally studied. The new antifungal material corresponds to a nanocomposite, ie that composite materials combining different nature where one has nanometric dimensions. The preparation of this nanocomposite using the existing prosthesis as acrylic polymer matrix and particles of nanometric copper (CuNPs) as the antimicrobial component, is the central aspect of the invention.
The preparation of this nanocomposite materials considered the lowest suitable for incorporation of the matrix CuNPs conditions, but everything conjugated anti-microbial properties, aesthetic (color), mechanical and cytocompatibility the resulting material. The traditional method for preparing polymeric nanocomposites is the physical mixing of the polymer melt or dissolved in a solvent with nananopartículas (ex situ method). Making a dental prosthesis is a polymerization process occurring on a disposable material, which holds dental patient record given by the position of artificial teeth. Thus, using the ex situ method require dissolve previously manufactured dentures reason that is not feasible for this application.
In a previous work by the inventors (Correa, S., Preparation of acrylic resins loaded with copper nanoparticles and its antimicrobial properties against Candida albicans, 2012 Institute of Dental Sciences, University of Chile. Santiago de Chile), was studied CuNP incorporating acrylic dentures. methyl methacrylate monomer and an organic solvent as reducing agents used in this study to allow in situ formation of copper nanoparticles during the polymerization process by self-curing acrylic. It was observed that the nanocomposite filled acrylic with CuNPs material has a strong antimicrobial activity against Candida albicans, allowing inhibit growth of Candida albicans in the denture over 80% compared to control. This effect was found to be proportional to the content of the composite CuNPs. The antimicrobial effect of acrylic (CuNP / PMMA) was sustained over time, indicating that CuNPs and / or copper ions are gradually released to the medium . The method developed as well as new material, they appear as a promising alternative to control subprótesicas infections caused by Candida albicans. Additionally, the presence of copper in the prosthetic material, could also have a control over the development of periodontal pathogens. Previous studies from our laboratory group have developed gels biopolymer loaded with copper nanoparticles, which are able to inhibit the growth of Aggregatibacter actinomycetemcomitans (Gonzalez JP, Synthesis of bactericidal materials based on metal and biopolymer nanoparticles for dental periodontal therapy. Institute . of Dental Sciences 2013, University of Chile: Santiago de Chile). This would indicate that the presence of copper nanoparticles in acrylic, and therefore their interaction with the oral cavity may reduce the growth of periodontal pathogens.
The approach to the development of this antimicrobial copper-based resin has a scientific and technological challenge from various viewpoints. The basis of the challenge is based on the need to develop nano particles of copper or nanostructured which are stable in the polymeric matrix used for dentures. For this it is necessary to find the best nanoparticle incorporate copper (size, nature, shape), in addition to improved methodology to prepare the polymeric composite. Furthermore, the composite must provide controlled release of copper ions at a rate that is less than the minimum required to avoid toxicity and near necessary to have a biocidal effect concentrations. All this, without altering the polymerization step of the resin in the present process of commercial preparation of the prosthesis. In the study of previous thesis, he worked with acrylic self-curing, so in this project thesis optimization process of preparing the nanocomposite is proposed conditions thermopolymerization, which is the process used commercially for the manufacture of dentures . It will also consider comparing the in situ process previously developed with the traditional process ex situ method. In the latter procedure, the CuNP is previously synthesized by another technique, and then incorporated into the polymer matrix. This new material would antlmlcroblanas properties against Candida albicans, inhibiting their growth, and thus, preventing or treating denture stomatitis. It is also expected that the new graft material present antimlcrobiana perlodontales activity against pathogens. The latter could have consequences in controlling infections perlodontales partially edentulous patients (denture wearers), and thus stimulate the perlodontal health of the remaining teeth, improving their prognosis mouth. Furthermore, the new prosthesis should maintain the structural properties of the original resin, without substantial alteration in color from the aesthetic point of view - dental. This raises the need to optimize the process of preparing the nanocomposite material prosthesis according to the different properties (antlmicroblanas, mechanical, color), related to particle type copper concentration, method of incorporation and distribution in the pollmérica matrix among other variables.
The present invention focuses on the preparation of a nanocomposite material based on copper nanoparticles and thermosetting pollmetilmetacrllato; with antlmicroblanas properties against Candida albicans; optimizing mechanical properties, and aesthetic cltocompatibllldad, which uses an in situ method of forming the nanocomposite, incorporating nanoparticles during the polymerization process. In this case the previously synthesized particles are incorporated in dispersing any of the reaction components (monomer, solvent), and then allowing polymerization to occur. The invention not only in situ nanocomposite preparation is proposed, but also the CuNPS is synthesized during the polymerization process. This process is proposed based on reducing properties possessed by the metllmetacrllato monomer, and could be enhanced by the addition of small fractions of any organic solvent, such as ethanol. Thus the CuNPs can be formed by the reducing action of the monomer on copper ion Built from a metal salt. Such processes in situ formation of the nanoparticle, allowing more efficient incorporation and a more homogeneous dispersion of the particles in the matrix of the nanocomposite. These aspects are known factors that favor bloactivas, mechanical and optical properties (color) of the composite obtained. Additionally it considered nanocomposite preparation using CuNPs previously synthesized by other methods. Here they will be used CuNPs commercially available and CuNPs supported on particles of a ceramic material. The latter approach also makes an important contribution from the scientific point of view.
Copper supported on ceramic matrices have a lower average density and a lower impact on the coloration of polymer composites.
Moreover, as part of the development of the present invention it has developed a method for the synthesis of nanostructured CuNPs on ceramic materials as zeolites or silica. Zeolites are crystalline aluminosilicates having a nanostructure consisting of pores, channels and cavities with nanometric dimensions sub. Thus, one can obtain a copper-zeolite material, wherein the metal nanoparticles are supported within the cavities of the ceramic material. The synthesis procedure of CuNPs supported ceramic particles, biocompatible reducing agents used, which makes these materials particularly suitable for most biomedical applications.
Because the state of the art no studies preparation of dental acrylic CuNPs reported are of interest all the techniques and synthesis strategies for the preparation of dental acrylic with antimicrobial properties. Application of these procedures extends to any type of dental, such as those used in restoration composites, adhesives restoration, orthodontic adhesives, sealants, glass ionomers or acrylic resins; applications in which the antimicrobial control is an aspect of current interest.
The dental prosthesis made with the nanocomposite material has a strong antimicrobial effect against C. albicans and Streptococcus mutans due to the recognized antimicrobial properties of copper, particularly being effective antifungal. According to the principles of nanotechnology, copper particles with nanometric size should have a better activity, which means that low contents of the metal can have a significant antimicrobial effect. The antifungal properties of the nanocomposite are given by the fungicidal or anti-fouling (release) comprising copper. These effects occur by controlled release of the copper particles from the polymer matrix by exposing the nanocomposite with the aqueous medium. Commonly polymeric matrices also suffer erosion in contact with the physiological medium, which would also facilitate the release of copper from the surface of the nanocomposite. It has been further shown that water molecules can penetrate between the polymer chains, oxidizing the nanoparticles, producing diffusion and subsequent release from the polymer matrix as ions. The use of different advanced techniques such as XPS characterization supplemented with copper release studies in aqueous medium and microbiological tests; cause you can come to understand quite closely, antifungal mode of action of the new material.
Current solutions to the problem of denture stomatitis mainly focus on applying topical antifungals on the affected mucosa. Although treatment with antifungals can remedy infection, topical application procedures are not always properly followed by patients, especially those belonging to the elderly. Topical antifungals also particularly characterized by having unpleasant tastes, create discomfort during use and maintained for a short time in contact with the oral mucosa. Because of the disadvantages of topical antifungals, as well as the limitations of patients to follow the protocols for implementing the antimycotic; new alternative solutions to this problem of oral health are required. aimed at preventing disease development strategies are always more advisable for the health of the population. In this context the development of dental prostheses with antimicrobial properties appears to be an attractive alternative for the control of oral infection. The dental device made of a material specially formulated to have an antimicrobial effect against C. albicans, should significantly reduce the appearance of stomatitis caused by that pathogen. Therefore, the new material develops prosthetic elements that currently delivers nanotechnology. It is based on controlling matter on a nanometer scale (10 ~ 9m) to generate products with improved or new properties, discipline is globally affecting various fields of industrial and social impact. In the dental field, the influence of nanomaterials can be found for example in the current nanocompositas dental restorative resins, which have improved durability and aesthetic properties.
In recent years it has been found that copper nanoparticles are more effective as antimicrobial agents microparticles, which opens opportunities in the field of nanotechnology antimicrobial materials. This justifies the use of these particles as agents to be incorporated in plastic matrices, as seen in other systems such as polymer / silver. Although the antimicrobial properties of copper nanometric are known in other fields of application it is not known use in dental products, which is a component of research and innovation of this proposal.
The antimicrobial material is a nanocomposite that is a composite material that combines materials of different nature (metal and polymer) and wherein one of them has nanometric dimensions. The nanocomposite is constituted by a matrix of polymethylmethacrylate (PMMA), which will disperse various copper nanoparticles (CuNPs). The matrix selection is based on its wide use in applications prosthesis, so as to facilitate their incorporation into the market.
The present invention focuses on developing the most suitable technology for manufacturing the nanocomposite material conjugating variables preparation with antimicrobial properties against C. albicans; as well as its mechanical and aesthetic characteristics. The process of forming the nanocomposite considered in situ synthesis of CuNPs during polymerization of PMMA, although alternatively ex situ incorporation of the metal particles will also be considered, varying the percentage of filler in the matrix. The goal is to find the best particle contents in the polymer matrix and the most appropriate method for incorporation, considering the antimicrobial, aesthetic and mechanical behavior of the resulting nanocomposite material
In Figure 1 the process of preparing the nanocomposite is diagrammed. In the in situ method is used as precursor of CuNPs a copper salt, while processes ex situ CuNPs pure powder or a ceramic material such as zeolite or silica modified with copper Generally, in situ method is used the precursor the CuNP is incorporated into the monomer before being mixed with the polymer according to the traditional method of preparing acrylic prosthesis and cause polymerization or curing by self heat. These different methods to optimize the process to obtain the antimicrobial resin way to find the best formulation, and are the foundation of innovation showing the present invention as different aspects such as coloring is contemplated. In particular, copper supported on an inorganic matrix has on average a low density and lower impact on the color of the matrix.
Figure 1 . Scheme of the synthesis procedure of nanocomposite materials CuNP / PMMA. It is considered that by adding copper nanoparticles to the resin which is currently used in prostheses, a new antimicrobial material is generated with similar aesthetic and resins currently used mechanical properties. This since copper is an effective antimicrobial agent, and its more effective than their microparticles nanoparticles. Furthermore, when the nano-sized particles, they do not significantly affect the performance of the original matrix. All this justifies our approach based on nanotechnology.
Regarding the mechanism of antimicrobial action of the new nanocomposite material shows that it has an antimicrobial action primarily by the release of copper ions to the medium (Figure 2). Ions are released steadily from within the polymer matrix, which exert a fungicidal action on the microorganisms which contact with the material surface or located in the vicinity of the interface. This mechanism reduces the viability and adherence of the pathogen on the surface of the prosthetic material and the mucosa is in contact with the dental device. These properties of the new material prosthesis create antimicrobial conditions for preventing or treating infection subprosthetic.
Figure 2. Possible mechanisms of action of antifungal nanocomposite CuNP / PMMA
With respect to the existing regulations for the use of copper in humans, the Food and Drug Administration (FDA) considers maximum levels of copper in bottled drinking water of 1 mg / mL (FDA 2001). Furthermore the Institute of Occupational Medicine (IOM) reports an allowable recommended dietary allowance (RDA) of 0.9 mg / day and a maximum tolerable intake of 10 mg / day. In the present invention, the nanocomposites have a copper content of between about 30-150 mg / g. The acrylic material of a denture base has a mass of about 10 g, whereby a prosthesis made with nanocomposite has maximum copper from 0.3-1, 5 mg. This suggests that the amount of copper released into the oral cavity must be found under the recommended levels some regulations. In addition, studies of cytotoxicity of each of the formulated materials, so as to optimize the activity antmicrobiana nanocomposite according biotolerable levels and indicated by existing regulations copper were performed.
From the methodological point of view the composite is synthesized by various synthesis strategies in-situ. In such strategies, copper, either as precursor to subsequent nanoparticle or particle and synthesized, is mixed with the monomer to conduct polymerization together. In a first strategy both the polymer and nanoparticle are synthesized in a single step by adding a precursor of copper and monomer; in the second strategy the nanoparticle is synthesized and mixed with the monomer for further polymerization. In the latter strategy two forms of copper nanoparticles was studied: metal and copper supported on a ceramic matrix.
Since the antimicrobial effectiveness and toxicity are related to the release of copper ions, we seek to find that methodology to better control the rate of release of ions without altering the polymerisation process or the final properties of the resin : mechanical, aesthetic (coloring) and cytocompatibility.
DETAILED DESCRIPTION OF THE FIGURES.
Figural to display an image of SEM of copper nanoparticles (CuNP) synthesized in situ in the acrylic monomer, wherein the average size of CuNP is 40 nm and nanometric nature was also confirmed by plasmon surface resonance detected by the band characteristic absorption at 593 nm (see Fig. 1 b). Fig. 1 b shows a SEM picture of copper nanoparticles synthesized by the in situ method in the acrylic monomer (a) and absorption spectrum indicating the plasmon resonance surface.
Figure 2a, 2b and 2c shows the presence of copper nanoaprtícuas acrylic matrix nanocomposites which was confirmed by elemental mapping EDX, being a relatively homogeneous metal over the entire polymer matrix distribution copy. FTIR analysis of the material indicated that spectra nanocomposites exhibit all the bands corresponding to the spectrum of PMMA, indicating that the chemical structure of the polymer is not altered by the incorporation of the metal nanoparticles. Wherein 2a shows an SEM image of a nanocomposite CuNP / PMMA, Figure 2b shows an EDX elemental mapping confirming the distribution of copper in the acrylic matrix; and Figure 2c shows a FTIR-ATR acrylic PMMA nanocomposites and materials analysis.
FIGURE 2a 2b 2c
Figures 3a and 3b shows that nanocomposites materials with different contents of CuNP maintain the original mechanical properties of PMMA acríllco control. Wherein 3a shows the mechanical properties of flexural strength of PMMA and acríllco nanocompósltos with different content CuNP; and Figure 3b shows the mechanical property of the compression module of acríllco PMMA and with different content nanocompósltos CuNP:
Results antimlcrobiana activity nanocompósltos materials against C. albicans was expressed as an ability to inhibit growth of the microorganism on its surface on the number of colonies grown on the material PMMA control without CuNP, which is defined by the following expression:
(CFUpfrm ^ ^ CUNP CFU / PMMA ^)
Inhibition capacity rr¡ = ~~: -; x 100
CFU PMMA: hormadoras units colony grown on the surface of PMMA acrylic. ■ CFUPMMA colony forming units grown on the surface of nanocomposite CuNP / PMMA.
Figure 4 shows the inhibition capacity nanocomposite materials against C. after 48 hours of prepared incubation albicans with different contents of CuNP, where it is seen that the nanocomposite acrylic prepared prostheses have a range of copper content between 0 01 5 to 0.068%, and which produce a range of percent inhibition between 65% and 92%, wherein the maximum growth inhibition of C. albicans CuNP containing 0.045% is obtained.
0.015% 0.045% 0.053% 0.060% 0.068%
% Copper content
Figure 5 shows the inhibition capacity nanocomposite materials (CuNP / PMMA) against C. albicans at different incubation times, where it was found that the antimicrobial effect on the surface of the material is extended with time.
Incubation time [days]
In order to elucidate the possible mechanism of antimicrobial action of nanocomposite materials, the material surface 6 shows the XPS spectrum of the surface of acrylic nanocomposite CuNP (0.045%) / PMMA was analyzed by XPS spectroscopy FIG. The analysis results indicate no detectable copper atoms in the material surface; whereby the antimicrobial effect should be attributed primarily to the amounts of copper released into the product of the diffusion of ions or copper particles from the acrylic matrix to the environment.
Figure 7 shows the release of copper versus time from acrylic nanocomposites in artificial saliva (pH 6.5), wherein it is seen that the materials release very low concentrations of copper to the medium, with maximum values around 5.8 x10 "3 ug / mL after 35 days after incubation in artificial saliva. However, these low levels of copper released are sufficient to produce the observed antimicrobial and while maintaining the biocompatibility of the new prosthetic material.
Incubation time (days)
In Figure 8 the viability of human fibroblast cells cultured at different incubation times with the current acrylic graft material (PMMA) and the nanocomposite CuNP / PMMA measured by MTS assay mitochondrial activity occurs. It can be seen that the cell viability on the nanocomposite CuNP / PMMA is equivalent to the current observed on PMMA acrylic prosthesis. These results demonstrate that the incorporation of the acrylic CuNPs not alter its characteristics cytocompatibility.
In the preparation process antlmlcroblanos acríllcos it can also extend in the preparation of different acríllcos materials dental use resins such as dental restoration, adhesive resins restoration or orthodontic brackets, sealants Occlusal and fissures as ionomers glasses modified resin. These materials are prepared using different monomers acríllcos to MMA such as Bls- GMA, TEGDMA, UDMA, HEMA or PENTA and can be polymerized by photocuring or self-curing by a dual system. TABLE 1 capabilities inhibition of S. mutans bacteria cariogénlca for different dental materials prepared nanocompósltos shown by ex situ process CuNPs incorporation.
Dental material S. mutans (%) ± SD
Acríllco prosthesis 97 ± 2
dental restoration resin 97 ± 2
99 ± 3 Dental Adhesive
Dental sealant 99 ± 3
Glass ionomer 95 + 4 acríllco dental materials nanocompóslto CuNP / PMMA also showed inhibitory capacity against the bacteria agreggatibacter actinomycetemcomitans (93 ± 3%), a representative pathogen gingivitis and periodontitis.
The process of preparing the nanocomposite CuNP / PMMA can also be used for producing bone cement with antimicrobial properties. Bone cement based self-curing PMMA is used in orthopedics for fixing hip prosthesis, knee, shoulder and other joint prostheses. Bone cement based CuNP / PMMA showed an inhibition capacity of 94% ± 3 against the bacterium Staphylococcus aureus, major pathogen responsible for periprosthetic infection.
The present invention aims to develop a polymeric material with copper nanoparticles (CuNP), for which the composite material was synthesized by different synthesis strategies ex situ and in situ. Wherein the composite can be prepared by the m ethod ex situ, i rpo nco rando the particu the Cu N Ps / Zeo or nanopartícu the copper (Cu NP) prepared ex situ by this or other methods.
In all these strategies, copper, either as precursor to subsequent nanoparticle or particle and synthesized; It is mixed with monomer (PMMA) to jointly carry out the polymerization. In a first strategy both the polymer and nanoparticle were synthesized in one step by adding a precursor of an organic copper salt [Cu (CH3 COO) 2] and the monomer; in the second strategy the synthesized nanoparticle was mixed with the monomer for further polymerization. This latter strategy is to study two forms of copper nanoparticles: metal and copper supported on a ceramic matrix. Because the antimicrobial effectiveness and toxicity are related to the release of copper ions, it is intended to find that methodology to better control the rate of release of ions without altering the polymerisation process or the final properties of the resin such as mechanical and aesthetic (color) cytocompatibility. EXAMPLES
In this example, the preparation of nanocompósltos CuNP / PMMA detailed by in situ synthesis nanocompósitoutilizando material or thermoset auto polymerization. Where aqueous solutions of copper acetate [Cu (CH3 COO) 2] of different concentrations (0.1 -0.8 M), preferably 0.6-0.7 M, is used to which 100 μΙ_ of solution of copper (Cu 2+) is added over 2 ml_ of absolute ethanol, the resulting mixture is added under constant stirring 2 ml_ of liquid methylmethacrylate monomer dental self or thermoset. The resulting solution is kept under constant agitation at temperatures between 50-70 ° C until the formation of nanoparticles (CuNP), which is displayed by the appearance of the red colouration taking the reaction mixture. Subsequently, said solution of liquid monomer charged with CuNPs, mixed with dental acrylic powder in a 3: 2 mass Acrylic: volume of monomer (PMMA) to carry out the polymerization reaction under conditions of self or thermoset as appropriate.
In this example, the preparation of composites CuNP / PMMA using supported CuNPS detailed. The composite material was prepared also using Cu N Ps previously supported on Particu as a materi l ico pottery decor. T he use of Cu N i ncl or comings Ps particu the icas pottery decor could improve coloring property of the composite: and provide different release kinetics of copper from the material.Furthermore: being a ceramic support: the density will be less than in the case of particles metál icas: so stabi ity problems can be solved and decantation. Suitable support materials zeolite particles were used (the nosyl umi icato crystalline nanoporous) and silica nanoparticles, for which, is uti ried u na Zeol naturally ita national origin (MO R) and nanopartícu the sIL ice on January 00 commercial nm. The Cu N tuples Ps will form in situ in the aterial m, for this purpose certain mass of MOR was contacted with a solution of 0.1 M copper acetate for 24 h at room temperature. Once completed the period of ion exchange, the zeolite was separated and washed by repeated cycles of centrifugation / dispersion. The material obtained was then dispersed in a reducing starch solution / ascorbic acid, and subjected to microwave by certain seconds. This training system CuNPs biopolymer was developed by our laboratory, as a method under the concept of "Green Chemistry" for the synthesis of metal nanoparticles more benign and compatible with biomedical applications. CuNPs particles / MOR were separated, washed and dried for use later in the process of preparing the composite CuNP / PMMA. The composite was prepared by the above-described ex situ method, the dehydrated particles incorporated CuNPs / MOR liquid methylmethacrylate monomer.
In this example, the preparation of composites CuNP / PMMA detailed by ex situ method of incorporating CuNP in dental acrylic self or thermoset, where used CuNPs 5nm powder and commercially available (Nanotech SpA, Chile). The CuNPs were added to the liquid monomer methylmethacrylate (4 mL) self or thermoset, CuNPs masses in the range of 0.79 to 6.28 mg, then dispersed in ultrasound for 10 minutes and then mixed with dental acrylic powder in a 3: 2 acrylic mass / volume of monomer (polymethylmethacrylate: with incorporated initiator) to result in the polymerization reaction), subsequently the polymerization is conducted under conditions of self or thermoset.
In this example the in vitro evaluation of the antimicrobial properties of the nanocomposites CuNPs / PMMA, for which a microbiological study is developed using ATCC 90029 Candida albicans strain, from which broth cultures are prepared at a concentration described 0.5 McFarland (1 -5 x10 6 CFU / mi). In the microorganism suspension of nanocomposite materials samples CuNPs / PMMA prepared with different contents of CuNPs incubated and samples of acrylic material without CuNPs as control (PMMA). The incubation period is 48 hours initially to S 37 C under aerobic conditions. The antimicrobial effect of the material is assessed by colony counting in the supernatant broth and on the surface of the materials. For the first case, dilutions of the culture broth in Sabouraud agar plates are seeded and incubated for 48 h at 37 ° C. Moreover, microorganisms adhered on the surface of the material, are removed by a solution of innocuous surfactant, then be seeded and incubated on agar and count UFC.
Additionally, the antimicrobial effect of the materials for an extended period of 10 days in contact with the microorganisms was evaluated.
In this example the release of copper from the tested material in order to explain the mechanism of antimicrobial activity of nanocomposites. These tests were performed by immersing a piece of each type of nanocomposite CuNP / PMMA in artificial saliva (KCI- CaCl 2 -2H NaCI-0-NaH 2 P0 4 2 -2H 2 0-Na 2 S-9H 2 0-urea) pH from 6.5 to 37 S C, every certain time intervals a sample of the supernatant fraction which was replaced with fresh artificial saliva was taken. The total copper concentration in the collected aliquots was determined by atomic emission spectrometry inductively coupled plasma (ICP-AES). From these concentrations the amounts released metal over time was determined. EXAMPLE 6
In this example the cltocompatlbllldad of nanocomposites materials was tested, for which was assessed by incubation in cultured fibroblast cells. Cell viability was determined by the spectrophotometric assay of mitochondrial activity MTS (3- (4,5- dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium) for 3 , 5 and 10 days of incubation with the material.
In the present example the manufacture of dental prostheses using the previously optimized depending on their composition nanocomposite material antimicrobial properties, mechanical and aesthetic (color) and cytocompatibility performed. For this purpose two different manufacturing protocols normally used by dental laboratories were used. The prostheses were manufactured in dental laboratory facilities, according to protocols established with respect to the conditions of temperature, time and pressure thermoset; and the type of trays, printing materials, muffles, and other elements used for the design of the prosthesis according to patient characteristics. Manufactured prostheses are evaluated according to criteria dental regarding the mechanical properties of the acrylic based stability of artificial teeth, aesthetic characteristics, among others.
In this example, the preparation of nanocomposites CuNP / acrylic ex situ by a method of incorporating CuNPs resin dental restoration is detailed. The CuNPs powders are incorporated into a system or dual curing acrylic-based monomers, such as Bis-GMA, TEGDMA, UDMA or another, which may contain a micro or nanofiller based ceramic particles. 0.045% by weight - CuNPs concentrations are incorporated, preferably in the range 0.015. The resulting mixture is treated by ultrasound for 1 0 minutes, and then perform the polymerization reaction using LED for 40 seconds in the presence of camphorquinone as a photoinitiator.
In this example, the preparation of nanocomposites CuNP / acrylic detailed preparing nanocomposites CuNP / ex situ by a method of incorporating into an adhesive CuNPs resin system dental restoration. The CuNPs powder are incorporated in adhesive systems based on acrylic monomers such as UDMA or PENTA curing or dual. 0.045% by weight - CuNPs concentrations are incorporated preferably in the range 0.015. The resulting mixture is treated by ultrasound for 30 seconds, and then effecting polymerization reaction by applying light LED 10 to 30 seconds in the presence of camphorquinone as a photoinitiator or by dual polymerization.
In this example, the preparation of nanocomposites CuNP / acrylic adhesives using acrylic orthodontic by ex situ method of incorporating CuNPs detailed. The CuNPs powder are incorporated in adhesive systems for cementing orthodontic brackets based on acrylic monomers such as TEGDMA, Bis-GMA, UDMA, HEMA or photo or cold curing. CuNPs concentrations are incorporated preferably in the range 5-0045 0.01% by weight. The resulting mixture is treated by ultrasound for 30 seconds, and then carry out the polymerization reaction using LED for 10 seconds in the presence of camphorquinone as a photoinitiator or by autopolymerization.
In this example, the preparation of nanocomposites CuNP / acrylic detailed by ex situ method of incorporating CuNPs using modified ionomer glass photopolymerizable acrylic resin used as a bonding agent and restorative material temporary teeth and permanent teeth in as provisional. The CuNPs powder are incorporated in the liquid ionomer glass photo or self-curing at concentrations preferably in the range 5-0045 0.01% by weight. resulting Lamezcla is ultrasonically for 30 seconds, and then carry out the polymerization reaction using light LED 10 -30 seconds in the presence of camphorquinone as a photoinitiator or through self-curing polymerization.
In this example, the preparation of nanocomposites CuNP / acrylic detailed by ex situ method of incorporating CuNPs in sealing pits and fissures applied to occlusal surfaces of molar teeth that are particularly susceptible to the accumulation of plaque and the subsequent development caries. The CuNPs powder are incorporated in the glass sealants based on acrylic monomers such as Bis-GMA TEGDMA or picture or self-curing at concentrations preferably ranging from 0.015 to 0.045% by weight. The resulting mixture is treated by ultrasound for 30 seconds, and then carry out the polymerization reaction using light LED 10 -30 seconds in the presence of camphorquinone as a photoinitiator or through self-curing polymerization.
In this example, the preparation of composites CuNP / PMMA by an ex situ method of incorporating CuNP acrylic bone cement used in orthopedic fixation, such as hip, knee, shoulder and other joint prostheses detailed prosthesis. The CuNPs are incorporated in 4 mL of the liquid fraction monomer / activator autocure in amounts of from 0.79 to 6.28 mg, then ultrasonically dispersed in 1 0 minutes and then mixed with acrylic bone powder in a 3 2 acrylic mass (grams): monomer volume (mL). Subsequently the polymerization is conducted under conditions of self-curing.
Priority Applications (2)
|Application Number||Priority Date||Filing Date||Title|
|Publication Number||Publication Date|
|WO2017113030A1 true true WO2017113030A1 (en)||2017-07-06|
Family Applications (1)
|Application Number||Title||Priority Date||Filing Date|
|PCT/CL2016/050079 WO2017113030A1 (en)||2015-12-30||2016-12-29||Method for producing orthopaedic and dental acrylic materials having antimicrobial properties, using copper nanoparticle technology|
Country Status (1)
|WO (1)||WO2017113030A1 (en)|
|Publication number||Priority date||Publication date||Assignee||Title|
|US20140288171A1 (en) *||2008-12-16||2014-09-25||The Board Of Regents Of The University Of Texas System||Acrylic polymers containing metallic nanoparticles|
|WO2015006087A1 (en) *||2013-07-08||2015-01-15||3M Innovative Properties Company||Hardenable dental composition containing a mixture of agglomerated and aggregated nano-particles, kit of parts and use thereof|
Patent Citations (2)
|Publication number||Priority date||Publication date||Assignee||Title|
|US20140288171A1 (en) *||2008-12-16||2014-09-25||The Board Of Regents Of The University Of Texas System||Acrylic polymers containing metallic nanoparticles|
|WO2015006087A1 (en) *||2013-07-08||2015-01-15||3M Innovative Properties Company||Hardenable dental composition containing a mixture of agglomerated and aggregated nano-particles, kit of parts and use thereof|
Non-Patent Citations (5)
|Vianna et al.||In vitro evaluation of the antimicrobial activity of chlorhexidine and sodium hypochlorite|
|Yoshida et al.||Characterization and inhibitory effect of antibacterial dental resin composites incorporating silver‐supported materials|
|Teughels et al.||Effect of material characteristics and/or surface topography on biofilm development|
|Holmes||Clinical reversal of root caries using ozone, double‐blind, randomised, controlled 18‐month trial|
|Allan et al.||Antibacterial activity of particulate Bioglass® against supra-and subgingival bacteria|
|US5160737A (en)||Liquid polymer composition, and method of use|
|Zhang et al.||Dentin enhances the antibacterial effect of mineral trioxide aggregate and bioaggregate|
|Kumar et al.||Nanotechnology in dentistry|
|Pai et al.||Evaluation of antiplaque activity of Azadirachta indica leaf extract gel—a 6-week clinical study|
|Imazato||Antibacterial properties of resin composites and dentin bonding systems|
|Wright et al.||Effects of metronidazole on Porphyromonas gingivalis biofilms|
|Spahr et al.||Effect of the enamel matrix derivative Emdogain® on the growth of periodontal pathogens in vitro|
|Rosenbloom et al.||Salivary Streptococcus mutans levels in patients before, during, and after orthodontic treatment|
|Stanislawski et al.||Factors responsible for pulp cell cytotoxicity induced by resin‐modified glass ionomer cements|
|US20100209515A1 (en)||Electricity-generating particulates and the use thereof|
|Shrestha et al.||Nanoparticulates for antibiofilm treatment and effect of aging on its antibacterial activity|
|Peng et al.||Silver compounds used in dentistry for caries management: a review|
|Allaker||The use of nanoparticles to control oral biofilm formation|
|US20030220416A1 (en)||Curable compositions with antimicrobial properties|
|Hojati et al.||Antibacterial, physical and mechanical properties of flowable resin composites containing zinc oxide nanoparticles|
|Osinaga et al.||Zinc sulfate addition to glass-ionomer-based cements: influence on physical and antibacterial properties, zinc and fluoride release|
|Zhang et al.||Effects of dual antibacterial agents MDPB and nano-silver in primer on microcosm biofilm, cytotoxicity and dentine bond properties|
|Wang et al.||Dental materials with antibiofilm properties|
|García‐Contreras et al.||Perspectives for the use of silver nanoparticles in dental practice|
|Melo et al.||Nanotechnology-based restorative materials for dental caries management|
|121||Ep: the epo has been informed by wipo that ep was designated in this application||
Ref document number: 16880234
Country of ref document: EP
Kind code of ref document: A1